Regulating synaptic activity within a suitable working range is important for the stability of neuronal function. Homeostatic synaptic plasticity (HSP) utilizes compensatory feedback mechanisms to combat excessively low or high firing rates despite fluctuations in neuronal input, but underlying molecular pathways are not well understood. We discovered that chronic inactivity induces the formation of giant excitatory synapses specifically in proximal dendrites, with no morphological changes detected at distal synapses. These enlarged proximal dendritic structures were composed of complex clusters of synapses arranged on unusually large and elaborate dendritic spine-like protrusions, and were enriched for AMPARs and N-type calcium channels, but not NMDA receptors. Taken together, these properties were reminiscent of [unreadable]thorny excrescences,[unreadable] large branched dendritic spines of unclear function on proximal dendrites of hippocampal CA3 pyramidal neurons and mossy cells in vivo. Thus, our overarching hypotheses are that complex synapses represent the in vitro correlates of thorny excrescences, and that thorny excrescences therefore act as homeostatic control devices in independently tunable proximal dendritic zones. In this proposal, we will pursue the following Specific Aims: 1) Directly test homeostatic regulation of thorny excrescence formation in cultured neurons, hippocampal slices, and in vivo, and examine the ultrastructure of in vitro excrescences;2) Investigate the molecular mechanisms that regulate thorny excrescence formation, focusing in particular on the role of Cav2.2 [unreadable] Stargazin interaction as an anchor for AMPA receptor delivery and the role of CaMKIIb in promoting assembly of this ternary complex;and 3) Analyzing the functional properties of proximal dendritic cluster synapses using electrophysiological techniques. The results obtained will be important for understanding neuronal responses to extreme changes in synaptic activity levels, and will have clinical significance for various neurological disorders involving aberrant brain activity.